Label-free biosensors based upon detecting shifts in wavelength, coupling angle, or the magnitude of optical resonances have become an effective and commercially viable means for characterizing bimolecular interactions for applications in drug discovery research, protein biomarker diagnostic testing, pharmaceutical manufacturing, and environmental monitoring.
Examples of prior art in this area include Narayanaswamy, R. & Wolfbeis, O. S. Optical sensors: industrial, environmental, and diagnostic applications. (Springer, Berlin; New York; 2004); Cunningham, B. et al. A plastic colorimetric resonant optical biosensor for multiparallel detection of label-free biochemical interactions. Sens. Actuators, B 85, 219-226 (2002); Homola, J., Yee, S. S. & Gauglitz, G. Surface plasmon resonance sensors: review. Sens. Actuators, B 54, 3-15 (1999); Armani, A. M., Kulkarni, R. P., Fraser, S. E., Flagan, R. C. & Vahala, K. J. Label-free, single-molecule detection with optical microcavities. Science 317, 783-787 (2007); Stewart, M. E. et al. Quantitative multispectral biosensing and 1D imaging using quasi-3D plasmonic crystals. Proc. Natl. Acad. Sci. USA 103, 17143-17148 (2006); Tazawa, H., Kanie, T. & Katayama, M. Fiber-optic coupler based refractive index sensor and its application to biosensing. Appl. Phys. Lett. 91,—(2007), and Zhang, Y., Chen, X. P., Wang, Y. X., Cooper, K. L. & Wang, A. B., Microgap multicavity Fabry-Perot biosensor. J. Lightwave Technol. 25, 1797-1804 (2007).
Desirable properties for such sensors include ease of fabrication over large surface areas, robust noncontact illumination/detection optics, the ability to perform many independent assays in parallel, and the ability to incorporate the sensor into common biochemical assay formats such as microplates or microfluidic channels. See Choi, C. J. & Cunningham, B. T., A 96-well microplate incorporating a replica molded microfluidic network integrated with photonic crystal biosensors for high throughput kinetic biomolecular interaction analysis, Lab on a Chip 7, 550-556 (2007); and Cunningham, B. T. et al. Label-free assays on the BIND system, J. Biomol. Screen. 9, 481-490 (2004).
Although label-free detection methods demonstrate detection resolution below 1 pg/mm2, they have not replaced fluorescence and enzyme-based assays requiring the highest levels of sensitivity. The ability to resolve exceedingly small changes in the adsorbed mass density is particularly important for assays requiring the detection of samples at low concentration, or the detection of biomolecules with low molecular weight, such as drug compounds.
To address these challenges, researchers have designed label-free biosensor structures with passive optical resonators that provide a Q-factor up to 108, so that smaller wavelength shifts may be resolved. See Armani, A. M. & Vahala, K. J., Biological and chemical detection using ultra-high-Q toroidal microresonators, Biophys. J. 29A-29A (2007); Chao, C. Y., Fung, W. & Guo, L. J., Polymer microring resonators for biochemical sensing applications, IEEE J. Sel. Top. Quantum Electron. 12, 134-142 (2006).
The drawbacks of extremely high Q-factor passive resonators include the requirement for precise optical alignment with the illumination source, and retaining sufficient dynamic range of wavelength shift to accommodate the detection of surface functionalization layers, immobilized ligands, and analytes.